Health Review

The role of medial prefrontal cortex in cognition, aging and

Parkinson disease
Lia de Oliveira Jereissati 1, Alexandre Almeida da Silva 1, Vitor Olímpio Coimbra 1, Amanda Rebouças Bezerra de
Menezes 1, Gabriel Felipe Gomes 4, Stéfani Lara Galvão 4, Roger Wilson Gonçalves de Oliveira 5, Nayla Lima dos
Santos 1, Pamella Mendes Martiniano da Silva Cardoso 6, Luciano Barroso de Albuquerque Filho 1, Camilla Costa
Sallem 1, Rafaella Iughetti da Costa 1, Lara Maria Fujita Vieira Lima 1, Micael Porto Portela Lima 1, Júlio César
Claudino dos Santos 1, 2, 3, 4, 5, *
1 Faculdade de Medicina, Centro Universitário Christus, UNICHRISTUS, Fortaleza, CE, Brasil.
2 Universidade Federal de São Paulo, São Paulo, SP, Brasil.
3 Laboratório de Neurociências, Departamento de Neurologia e Neurocirurgia, Universidade Federal de São
Paulo, São Paulo, SP, Brasil.
4 Centro Universitário Barão de Mauá, CUBM, Ribeirão Preto, SP, Brasil
5 Centro Universitário Fametro, Manaus, AM, Brasil.
6 Universidade Federal da Paraíba, João Pessoa, PB, Brasil.

* Correspondência: julio.santos@alu.ufc.br.

Citation: Jereissati LO, Silva
AA, Coimbra VO, Menezes
ARB, Gomes GF, Galvão SL,
Oliveira RWG, Santos NL,
Cardoso PMMS, Albuquer-
que-Filho LB, Sallem CC, Costa
RI, Lima LMFV, Lima MPP,
Santos JCC. The role of medial
prefrontal cortex in cognition,
aging and Parkinson disease.
Brazilian Journal of Clinical
Medicine and Review. 2023
Jul-Sep;01(3):28-40.
Received: 1 June 2023
Accepted: 27 June 2023
Published: 30 June 2023
Abstract: The prefrontal cortex (PFC) is a vital center for executive control, influencing cognition,
emotion, memory, and sociability. Specifically, the medial prefrontal cortex (mPFC), a part of the
PFC, monitors actions toward goals, aids decision-making, and regulates cognitive control. It
assesses outcomes relative to expected rewards, selects appropriate behavior based on continuous
performance analysis, and facilitates strategic adaptation in response to adverse results. Unfortu-
nately, these cognitive functions decline with age due to changes in neuroplasticity, especially in
neurodegenerative disorders like Parkinson's Disease (PD) and Alzheimer's Disease (AD). Neu-
rodegenerative diseases disrupt normal brain activity, leading to tissue atrophy and cognitive
impairment caused by degeneration and neuronal death. PD is the second most common neuro-
degenerative disease globally, characterized by a decline in neurotransmitters and dopaminergic
neuron death in the substantia nigra, along with the presence of Lewy bodies. Recognizing these
factors as risk factors for PD development is crucial. This article examines how aging affects cog-
nitive activities regulated by the mPFC, a pivotal region for critical cognitive functions. Through a
narrative review of literature published between 2010 and 2022 in the Medline (Pubmed) database,
the study explores the topics of "cognition and Parkinson's disease," "prefrontal cortex," and "cog-
nition and aging." By applying predetermined criteria, the review selects the most relevant articles
to provide a comprehensive understanding of cognitive deficits mediated by the mPFC in both
healthy and pathological aging.
Keywords: Prefrontal cortex; Cognitive deficits; Aging; Parkinson's Disease.

Copyright: This work is licensed
under a Creative Commons
Attribu-tion 4.0 International
License (CC BY 4.0).
1. Introduction
The prefrontal cortex (PFC) is a neocortical area that, along the evolutionary process,
was more developed in human beings and in primates [1]. The PFC is responsible for
transmitting and receiving information originated from various encephalic regions and
presents itself as the center of human personality, an area that plays an important part in
cognition, emotion, memory, and sociability of an individual, besides being able to sup-
press undesired actions [2, 3]. The damage of this region, caused by cerebrovascular ac-

Braz. Journal of Clinical Medicine and Review, 2023, 1, 3, 19-27. https://doi.org/10.52600/2965-0968.bjcmr.2023.1.3.19-27. www.bjclinicalmedicinereview.com.br
Brazilian Journal of Clinical Medicine and Review 2023, 1, 3, 28-40 29 of 40

cident, trauma, neurodegeneration, as well as the aging process, leads to a decline in the
cognitive process4. The medial prefrontal cortex (mPFC) associated to the mediodorsal
thalamus, hippocampus, and nucleus accumbens (NAc) are regions that perform a con-
trol of the cognitive domains, such as memory, attention, language, motivation and ex-
ecutive functions [2, 5]. One of many functions of the mPFC is selecting the convenient
behavior in adequate timing, aiming to generate a procedural harmony of when and how
to act in a determined situation, in other words, a temporal control of the action, besides
also acting in the adaptive behavior in daily uncertain environments [6]. Thus, the cog-
nitive functions cited above are compromised as the age increases. In part, this occurs
due to the modifications in the neuroplasticity process in the aged brain [7]. These alter-
ations are observed, mainly, in neurodegenerative pathologies, such as Parkinson's dis-
ease (PD) and Alzheimer's disease (AD), generating more significant motor and cognitive
dysfunctions in the individuals [2].
Aging is a natural process, caused by numerous complex factors that manifest a
progressive decline of normal physiological functions as time goes on. This phenomenon
increases the probability of developing various diseases, such as cancer, metabolic dis-
orders, and neurodegenerative diseases (ND) [8]. As years go on, it is expected that the
elderly population, in other words, above 65 years-old, present some cognitive decline
due to the aging process or to some associated dementia [9]. Thus, it is important to re-
port that dysfunctions in the communication between neurons, the increase of oxidative
stress and of neuroinflammation, the altered intracellular signalization, as well as the
decreased neurogenesis and modified synaptic neuroplasticity, are the main factors to
generate a significant compromise in the cognitive domains [7].
Neurodegenerative diseases are defined as illnesses that mitigate normal brain ac-
tivity, being commonly accompanied by nervous tissue atrophy, as well as the cognition
decrease, that get worse with the progression and chronification of the diseases [10].
These pathologies, in general, are not curable and are debilitating, having consequently
the degeneration and neuronal death, manifesting itself through bradykinesia, resting
tremor, intestinal dysfunction and sleepiness [11]. Parkinson's disease is considered the
second most prevalent neurodegenerative disease after Alzheimer's disease. It is esti-
mated that PD is present in 0,3% of the general population, males being two times more
susceptible to develop this pathology when compared to women [12], and its incidence
varies from 5/100.000 to more than 35/100.000 new cases a year, besides increasing from 5
to 10 times in the sixth until the ninth life decade, which proves the impact of aging as a
risk factor to develop these diseases [13]. Additionally, PD is characterized by a modifi-
cation in the neurotransmitters with the deterioration of substantia nigra, which repre-
sents the death of dopaminergic neurons, associated with the presence of Lewy bodies
[11, 14]. For many decades, the association between aging and Parkinson's disease has
been recognized by the scientific community; therefore, aging is characterized as a risk
factor to develop PDDP [15].
Therefore, it is evident that the medial prefrontal cortex is very damaged in neuro-
degenerative diseases because these pathologies alter the brain activity and are associ-
ated, intrinsically, to the aging process of the population. It is fundamental to understand
the role of this region in the cognitive functions that are altered in the senescence and in
Parkinson's disease, so that the studies related to this problem are perfected. Thus, the
aim of the present study is to substantiate a literature review about the role of the medial
prefrontal cortex in the cognitive processes, aging and Parkinson's disease, and the ben-
efits of the non-pharmacological treatment, in other words, exercise, in this condition.

2. Methodology
A gathering of scientific literature was done, in the PubMed database, in the years
from 2010 to 2022, about Parkinson, aging and cognitive decline of the medial prefrontal
cortex. In the PubMed database, 321 articles were found using the association of the de-
scriptors "cognition [mesh terms] and parkinson disease [mesh terms]", besides "pre-
Brazilian Journal of Clinical Medicine and Review 2023, 1, 3, 28-40 30 of 40

frontal cortex and cognition and aging" in the years from 2010 to 2022, using the filters
“Review e Systematic Review”, of which 64 articles were selected after their title was read
(Figure 1). The second exclusion criterion was the reading of the abstracts, of which 33
were selected according with the theme that will be addressed. The exclusion criteria
were titles that were not associated with aging, Parkinson's disease and prefrontal cortex,
articles published in another language that wasn´t English and studies that were pub-
lished outside of the period from 2010 to 2022.
Studies with experiments related to animal models, even if pertinent to the subject,
were excluded. Besides, although the main theme of the present study is not associated
with Alzheimer's disease, some studies related to the association between aging and
Alzheimer´s were included for addressing cognitive decline in aging. Furthermore, 14
articles were selected through PubMed following a relevance for the synthesis of the
present study. Besides these, 15 articles were manually added from the reference list of
the eligible articles, totalizing 29 added articles. Finally, 62 original articles in English
(including reviews and systematic reviews) remained (Figure 2).

Figure 1. Flowchart of the article selection.

Brazilian Journal of Clinical Medicine and Review 2023, 1, 3, 28-40 31 of 40

Figure 2. Resume of the role of medial prefrontal cortex in cognition, aging and Parkinson disease.

3. Results (Review)

3.1 The role of the medial prefrontal cortex in cognition activity

The right stimulation can evoke different familiar reactions in a fast and automatic
way through simple and stereotyped behaviors, known as bottom-up processing. On the
other hand, the diversification of behavioral possibilities demands more flexible patterns
of interaction between stimulus and answer16. However, this repose flexibilization en-
Brazilian Journal of Clinical Medicine and Review 2023, 1, 3, 28-40 32 of 40

hances the disorder risks, needing a coordination of attention and decision making [4,
16].
The simultaneous and coordinated operation from the numerous cortical and sub-
cortical structures focused on one aim is known as cognitive control and acts through a
top-bottom processing [17] (Figure 3). Cognitive control consists, generally, of main-
taining active the representation of relevant stimuli and of the goal, evaluating if the ob-
tained results are adequate to the objective and doing possible necessary adjustments.
Thus, in case the given answer is not in agreement with the objective, through cognitive
control it is possible to suppress actions or thoughts regulating the behavior [18]. The
executive control of behavior, emotions, thoughts, planning and intentionally flexible
decision making receives the name of executive functions, acting through the control of
the cognitive domain [19]. Generally, cognitive flexibility, inhibiting control, attention,
working memory and decision making compose the executive functions [4]. Many
structures participate in this processing, but the prefrontal cortex (PFC) is consistently
pointed out as the command center of executive control, receiving, and transmitting in-
formation from almost every sensorial and motor systems [16]. On the other hand, this
group of processes intrinsic to cognitive control are possible due to working memory,
which consists in the temporary storage of information and its manipulation through
previous knowledge focused on one goal, being essential for learning and problem solu-
tion and having PFC as a neural correlate [20].
Besides, some aspects of cognitive control, such as attention and decision making,
can be influenced by emotions. In contrast, cognition is also responsible for the regulation
of emotional answers [21]. Inserted in this mechanism, PFC acts in the regulation of bio-
genic amines liberation, such as dopamine, noradrenaline, and serotonin, that generate
humor alterations4. Other studies also linked cognitive control and PFC as intrinsically
related to social cognition that involves the elaboration of answers adequate to the
norms, values, and moral judgements [22]. Therefore, prefrontal lesions or neurodegen-
erative processes that damage PFC can cause personality changes, as well as in the other
functions previously mentioned [23].
A portion of the PFC named medial prefrontal cortex (mPFC) plays a key part in this
process of monitoring action focused on one goal. In particular, the anterior cingulate
cortex (ACC), a region that integrates the mPFC and regulates the detection of errors and
conflict monitoring [24]. The mPFC acts in the strategic adaptation of behavior adjusting
to adverse outcomes. Thus, mPFC is central for decision making and cognitive control,
monitoring the result in relation to the expected reward and selecting the adequate be-
havior to the situation through a continuous performance analysis. This flexible moni-
toring also demands an analysis and temporal adjustment of the action aiming the an-
swer precision and efficiency, modulation consistently associated with the activity of the
mPFC [25]. mPFC can be divided in subdivision named dorsomedial prefrontal cortex
(dmPFC) which communicates predominantly with neocortical regions; and ventrome-
dial PFC (vmPFC) whose communication predominantly occurs with limbic structures
and basal ganglia [21].
Outside this perspective, mPFC is responsible for rescuing long term memories
aiming to identify, in past experiences, the most adequate answer to each situation, di-
recting the behavior [26]. Therefore, this task involves selecting a convenient memory
and rejecting memories that are irrelevant to the task, which is only possible due to the
communication between the mPFC and hippocampus, mainly the ventral hippocampus
[27]. The motivation plays a fundamental role in orienting the behavior, in relation to the
search for rewards and when possible, errors or conflicts with the goal are identified [24,
26]. Other evidence points out the hippocampus´ s role in providing emotional aspects
and spatial contexts that project to the mPFC and subsidize the selection of an adequate
behavior to the context. On the other hand, the activity of mPFC also acts in the memory
consolidation, establishing information that was just obtained and facilitating the learn-
ing process. Studies suggest that during periods of greater inactivation, such as during
Brazilian Journal of Clinical Medicine and Review 2023, 1, 3, 28-40 33 of 40

sleep, the hippocampus is activated again and recreates an acquired memory, which also
generates its repetition in cortical structures. This process creates the consolidation of
acquired memory [26]. The synchrony between the mediodorsal thalamus and the mPFC
is associated to working memory, in which the inhibition of the mediodorsal thalamus
makes the action directed to the task more difficult and decreases the efficiency in the
selection of adequate behavior, as well as maintaining the representations of the stimulus
in the working memory [28] (Figure 3).
Additionally, the association between mPFC and nucleus accumbens is essential to
the modulation of the goal-directed behavior, mainly those directed to rewards. The re-
ward anticipation regulated by these structures originates from the comparison of in-
formation coming from emotional evaluations in the amygdala and spatial contextual-
ization in the hippocampus and leads to the planning and execution of adequate
goal-directed behaviors [29]. Besides, the activation of mPFC acts in the intermediation of
the attention allocation, which works through the neglect of irrelevant stimuli and focus
on the selected stimuli. Thus, the mPFC is fundamental for the efficiency of the executive
functions and its compromise can cause numerous damages in the control of these func-
tions [21].

Figure 3: Medial prefrontal cortex (mPFC) in executive functions control. The mPFC is divided in
vmPFC and dlPFC, involved in the control of cognitive flexibility, inhibition control, attention,
working memory and decision making. Abbreviations: ACC, anterior cingulate cortex; MDmc,
magnocellular subdivision of the mediodorsal thalamic nucleus; MDpc, parvocellular subdivision
of the mediodorsal thalamic nucleus; OFC, orbitofrontal cortex; PFC, prefrontal cortex; VMPFC,
ventromedial prefrontal cortex.

3.2 The relationship between medial prefrontal cortex and the aging process
The aging process is constantly accompanied by numerous neuroanatomical and
neurophysiological modifications [30]. Therefore, many of the cognitive deficiencies that
accompany the healthy aging process are explained by alterations in the medial pre-
frontal cortex, which plays a critical part in the cognitive decline in aging, including
cognitive flexibility and attention [4]. Studies show that even in healthy aging there is a
decrease in the connections of the mPFC with other cortical and subcortical areas leading
to decline [31]. Corroborating with these findings, a study performed in rodents demon-
strates the deterioration of the cognitive function during normal aging, in which occurs a
reduction in the velocity information processing when compared to younger rats [32].
In this context, evidence demonstrates notorious deficits related to age in a series of
cognitive functions mediated by the medial prefrontal cortex. This data is reinforced by
Brazilian Journal of Clinical Medicine and Review 2023, 1, 3, 28-40 34 of 40

findings in neurophysiological experiments in elder non-human primates, which pre-

sented damage in the working memory with reduced processing velocity [30].
Another important relation that should be highlighted is the decrease in volume and
thickness of gray matter in the mPFC, besides alterations in the pathways of the white
matter in healthy elders, in a way that the elderly with less volume of gray matter pre-
sented increased cognitive repercussion, impacting in the distraction and in the neural
suppression of irrelevant information, affecting memory. Similar results were found in
elders with decrease of the white matter’s integrity [33]. Thus, studies evidenced that any
structural or functional alterations in mPFC can lead to loss of the normal function [2].

3.3 Aging neurodegenerative-associated disorders involving the medial prefrontal

cortex
Neurodegenerative diseases (ND) are diseases of common cause and crescent mor-
bidity worldwide, mainly in elderly people, and are responsible for and atrophy of the
brain tissue leading to a decreased cognition capacity, diminishing the normal brain
function that tends to worsen with the chronicity of the condition [10, 12]. In addition to
that, phenotypes of neuroimage associated with aging, integrity of the white matter tract,
quantitative decrease of neurons in the prefrontal cortex (PFC) [34] are correlated with
aging, which is inherently connected to a deterioration of the cognitive function associ-
ated with a greater hypermetabolic activity [4]. Thus, considering that one of the main
functions of the medial prefrontal cortex (mPFC) is orienting the actions in time, having
decision-making as its central utility, since deciding which will be the moment of choice
is as important as selecting the appropriate actions in the context; in truth, the right action
at the wrong time usually will lead to terrible outcomes. Therefore, when these altera-
tions associated with neurodegeneration, vascular accidents or traumas occur in mPFC
can be observed mainly by deterioration of the executive function (defining goals, mem-
orizing, planning, and executing activities), besides also affecting the decision-making
process, which was evidenced by functional changes in working memory and cognitive
flexibility6. It is valid to highlight that the cited deficits are more accentuated and rapidly
progressive in the presence of ND, but aging itself is already responsible for some of
these alterations [30]. Amongst them is the deficiency of cognitive control, causing de-
pletion of sustained and selective attention, inhibitory control, working memory and
multitasking skills. Additionally, the arithmetic, the comprehension, the perception of
emotions and the emotional control, despite being associated with the PFC, do not pre-
sent decline associated with age. Therefore, cognitive decline is not present in all elderly
people [35]. Thus, studies provide evidence that neurodegenerative disorders alter the
mPFC’s function in a pathologic way, them being Alzheimer’s disease, Huntignton’s
disease and Parkinson’s disease4.
Alzheimer’s disease (AD) represents from 60% to 80% of all the dementia cases in
the world, being the most common manifestation of neurodegeneration and, corre-
sponding to about 24 million people globally. This prevalence is directly proportional to
aging, leading to an increase superior to 15 times when our observed sample is between
the age gap of 65 to 85 years old. In addition to this statistic, a north American study in
which the prevalence reaches 50% in people with more than 85 years old. In the face of
this data, it is easy to understand why AD is considered a disease of elderly people [12].
In a physiologic approach, there is deposition of extracellular plaques of beta-amyloid
peptide and formation of intracellular neurofibrillary tangles in the brain cortex, these
alterations will be clinically perceived as severe cognitive deficits, emotional depression,
and progressive motor dysfunction, besides loss of working memory, spatial memory
and anterograde memory [2].
Since the mPFC is responsible for working memory, its association with AD is clear.
Finally, it is worth mentioning that the hippocampus, a subcortical region of the brain
with close relation to the PFC, is responsible for learning, memory consolidation, affec-
tive behaviors, and mood regulation. It is believed that neurobiological alterations ob-
Brazilian Journal of Clinical Medicine and Review 2023, 1, 3, 28-40 35 of 40

served in the aged hippocampus, including increase in oxidative stress and neuroin-
flammation, altered intracellular signalization and gene expression, as well as reduced
neurogenesis and synaptic plasticity, are associated with the cognitive decline related to
the age. This region being one of the first sites of action of AD, probably the most docu-
mented and known characteristic of the disease is its visualized hippocampal atrophy,
mainly in magnetic resonances. Since the typical AD, in which there is memory com-
promise, represents about 60% of all cases and its main characteristic is the medial tem-
poral lobe atrophy (MTA) along with the atrophy of other temporal regions and atrophy
of the posterior cingulate/ precuneus. It is also important to highlight that this alteration
can be used to differentiate prodrome phases of AD in healthy individuals, as well as
excluding other diagnoses [36] (table 01). Thus, when taking into consideration its
communication with the PFC it is demonstrated that AD is a neurodegenerative disorder
related to aging [10].
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases,
standing only behind AD [12, 14]. Its prevalence is of 0,3% in the general population,
~1% in elderly people above 60 years-old and ~3% in elders 80 years-old or above (8 to 18
people from 100.000 per year), being most common in men (1,5 to 2 times greater than
women) with medium age of 60 years and life expectancy of 15 years after the diagnosis
[12]. This age association comes from the lack of dopamine and motor and non-motor
deficits of the disease, besides environmental and genetic factors, such as mitochondrial
dysfunction, oxidative stress, protein aggregation, damaged autophagy and neuroin-
flammation, which influence the risk of PD [13].
Its pathology acts through the presence of aggregates of alpha-synuclein in the
brain, containing Lewy Bodies in the brain’s substantia nigra, causing synucleinopathy
and the loss of dopaminergic neurons in the par’s compacta [13-14, 37], leading to a mo-
tor control disorder and some complications, such as the deterioration of cognitive func-
tions in 40% of cases, being a risk factor for dementia. Some of these cognitive alterations
are executive function, visuospatial abilities, and attention deficits [11]. This deterioration
could be, in part, by the alpha-synuclein spreading from substantia nigra pars compacta
to cortical structures, affecting, among other areas, the mPFC, progressing according to a
Braak stages (Figure 4).

Figure 4: Alpha-synuclein prion-like spreading. From substantia nigra pars compacta to cortical
structures, this misfolded protein causes neurodegeneration that, in chronic cases, may lead to
cognitive functions impairment.

Previously, it was believed that intellect maintained itself unaltered in PD, but re-
cent studies already demonstrated the prevalence of deficit and all kinds of cognitive
dysfunctions in the disease [37]. Thus, cognitive compromise in PD still has its physiol-
ogy as an incognito in current medicine, but the most accepted theories are that altera-
tions in the cholinergic, dopaminergic, and noradrenergic systems exist. Furthermore, the
Brazilian Journal of Clinical Medicine and Review 2023, 1, 3, 28-40 36 of 40

cognitive reduction affects 80% of patients with PD38, with a higher prevalence in pa-
tients with greater age and disease time [12]. Example of that is: 19-38% of patients pre-
sent dementia with a PD diagnosis of 10 years, which increases to 75% with additional 10
years of PD and, posteriorly, to 83% when patients have had PD for 20 years [12]. Thus,
the clinical evolution to dementia can be observed in manifestations such as working
memory and executive function deficiencies [38].
Finally, it is valid to highlight that there is a strong correlation between the neuro-
pathology of neurodegeneration and the gray matter’s atrophy, being considered a car-
dinal sign. Accordingly, we emphasize that this article addressed the main neurodegen-
erative diseases: AD and PD. The first presents prominent medial temporal lobe atrophy
(MTA) as a typical manifestation from the early stages of the disease, which has been
considered a useful biomarker in the pre-dementia states of AD that can diagnose and be
used as support. On the other hand, PD has a more heterogeneous pathophysiology, re-
sulting in numerous clinical manifestations. Therefore, the atrophy pattern was still not
established in a conclusive way for this disease, but recent studies identified specific at-
rophy patterns in the initial phase that can predict the malignant prognosis of PD, in-
cluding cognitive decline. Thus, new methodologic approaches showed that the ap-
pearance of cognitive deficits in the pathology can be associated with atrophy of areas of
cortical projection in the prefrontal and posterior cortical regions due to the loss of cho-
linergic nuclei in the prosencephalon [36].

3.4 Genetic Physiology of Parkinson's Disease

The advance in research demonstrated that the genetic scope was essential to better
the comprehension of Parkinson’s disease. From numerous investigated genes, the most
well studied include LRRK2, SNCA, VPS35, Parkin and PINK1. Thus, the mechanisms of
each cited gene interfere in the development of Parkinson’s disease [39]. However, it is
known that 5 to 10% of PD cases are related to genetic mutations, being LRRK-2 the most
frequently altered gene [40] and the most frequent cause in idiopathic PD cases, even
covering specific ethnic groups, given that in a sample of 248 affected patients from fam-
ilies with autosomal dominant parkinsonism, 7 were identified for transporting a LRRK-2
(G2019S) heterozygotic alteration, where such patients are from the United States, Nor-
way, Ireland and Poland [41-43]. Furthermore, in models of patients with sporadic Par-
kinson’s disease from the same populations, additional six patients with LRRK2 G2019S
were identified, and no alteration was found in individual control41. Besides, in another
great study, it was discovered that the frequency of mutations was of 1% amongst the
sporadic patients and 4% amongst the familial PD patients, but with the greatest fre-
quency of mutation amongst the Arabic and Ashkenazi–North African populations: 39%
and 38% amongst the arabic people from the north of Africa, and 10% and 28% between
the Ashkenazi jews with sporadic and familial PD, respectively [44, 45].
In this context, LRRK-2 contains numerous functional domains, including the I2020T
kinase domain, which has shown to have divergent effects, some increasing activity 46,
whilst others ended up demonstrating its decrease47, since the LRRK-2 superexpression
promotes neuronal toxicity, causing cell death, shortening of dendrites and, conse-
quently, neurodegeneration [48-50]. However, it is worth mentioning that such degener-
ative consequences were softened with chemical inhibitors of LRRK-2 or with inactive
kinase mutations that were inserted47. Furthermore, the substrates of LRRK-2 phos-
phorylation (except autophosphorylation) were also unknown until recently, however,
Rab GTPases (Rab5 and Rab7) substrates were identified not long ago, which affect sig-
naling cascades, degradation and endosomal traffic [51]. Sequentially, abnormal mor-
phologies and mitochondrial functions were observed amongst the LRRK-2 alterations,
as well as an abnormal accumulation in autophagic vacuoles, which are believed to be
bind through the 5'AMP-activated protein kinase (AMPK) [51]. Additionally, the inten-
sified activities of LRRK-2 increase the PD risk since the amplification of the kinase ac-
Brazilian Journal of Clinical Medicine and Review 2023, 1, 3, 28-40 37 of 40

tivity has been associated with nigrostriatal degeneration and with the formation of
Lewy bodies.
Secondly, when referring to the alpha-synuclein gene (SNCA), the pathogenicity
mechanism is still not totally clear, since the PD associated with SNCA demonstrates an
effect of gene dosage suspected of function gain. Thus, it was recently showed that an
increase in the number of SNCA copies leads to elevated levels of mRNA and wild-type
SNCA protein [52] and that such ampliation in the quantity of copies has been associated
with an earlier beginning of the disease, a more severe phenotype with some atypical
characteristics, including myoclonus, and a faster progression than in the duplication
[53]. Besides, a case of gene triplication reported by Singleton et al. had a notorious clin-
ical course because of its early beginning and a postmortem examination notable for a
prominently cortical and subcortical pathology [54]. Duplications were also reported in
numerous ADPD families [55] as well as in sporadic PD [56, 57] in which the reported
phenotypes include prominent psychiatric symptoms, including visual hallucinations
[55]. Thus, although the alteration in the SNCA gene is rare, the abnormal conglomerates
of alpha-synuclein protein are present in all the PD patients, in which such gene is the
main component of the Lewy bodies, the pathologic mark of Parkinson’s disease [58].
Finally, it is valid to highlight the PARKIN gene, whose pathogenicity mechanism
is also not totally clear. Parkin is an E3 ubiquitin ligase protein, which catalyzes the
ubiquitin transference to its specific target protein. Therefore, numerous target proteins
with highly variable functions were suggested as possible Parkin substrates, where a role
in the protein goal for proteasomal degradation was proposed [59]. Besides, PARKIN also
triggers a job with the PINK1 gene in the control of organelle quality through the activa-
tion of mitophagy in the context of mitochondrial damage60. The pre-exposed PINK1
gene is a serine/ threonine kinase, which also contains critical regulatory locations, where
its mutations are the second most common cause of ARPD after Parkin, with some su-
perposition with the Parkin phenotype. Its locus was identified for the first time in a Si-
cilian family (Marsala kindred) with four members affected by early beginning PD, with
course notorious for slow progression and a sustained response to Levodopa. Sequen-
tially, as suggested for the first time by Valente et al. through cell culture studies, PINK1
is localized in mitochondria imported to the segmentation pathway61 and its alterations
lead to a complete loss of kinase activity and are associated with an early beginning PD
[62].Thus, PINK1 works in a more prominent way along with Parkin in the mitophagy
activation, accumulating in the external mitochondrial membrane in the context of mi-
tochondrial damage [62].

4. Conclusion
Through the advances in medicine, there was an increase in life expectancy and in
the elderly population. In parallel, the prevalence of diseases related to age that led to
cognitive decline increased, amongst them Parkinson’s disease. In this review, we dis-
cussed how aging affects cognitive functions mediated by the medial prefrontal cortex,
which has a key role in a series of critical cognitive functions. Thus, this study will con-
tribute to a better characterization of cognitive deficits mediated by the mPFC in the
healthy and pathologic aging process.

Funding: None.
Research Ethics Committee Approval: The study was approved by the Directorate of Clínica Lu-
anda Medical Center under the direction of the Center for Advanced Studies in Medical Education
and Training at Agostinho Neto University. The preservation and confidentiality of patient infor-
mation were guaranteed, following all standards for research on human beings following the
Declaration of Helsinki on ethical principles for research on human beings.
Acknowledgments: None.
Brazilian Journal of Clinical Medicine and Review 2023, 1, 3, 28-40 38 of 40

Conflicts of Interest: The authors declare no conflicts of interest and no specific funding sources
for this work.
Supplementary Materials: None.

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